Abstract
Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus.
Highlights
Tinnitus, the perception of sound in the absence of acoustic stimulus, is frequently caused by exposure to loud sounds (Shargorodsky et al, 2010) and can be detrimental to the quality of life for millions of tinnitus sufferers (Roberts et al, 2010; Shargorodsky et al, 2010)
A Boltzmann fit of the KCNQ2/3 conductance–voltage (G–V) function showed that the Gmax of KCNQ2/3 currents was not different between 4 days sham- and 4 days noise-exposed mice (Figure 3C,E), but the V1/2 was shifted to more depolarized potentials in the 4 days noise-exposed mice (Figure 3C,D; ‘Materials and methods’). These results suggest that the reduction of KCNQ2/3 currents in 4 days noise-exposed mice is due, at least in part, to a depolarizing shift in the V1/2 of KCNQ2/3 channels, which is mechanistically similar to the reduction of KCNQ2/3 currents in tinnitus mice when assessed 7 days after noise exposure (Li et al, 2013)
Given that fusiform cells from non-tinnitus mice display control-level KCNQ2/3 currents 7 days post noise exposure (Li et al, 2013), our results suggest that it is the recovery in KCNQ2/3 channel activity, not the lack of reduction in KCNQ2/3 currents, which is linked with the resilience to tinnitus
Summary
The perception of sound in the absence of acoustic stimulus, is frequently caused by exposure to loud sounds (Shargorodsky et al, 2010) and can be detrimental to the quality of life for millions of tinnitus sufferers (Roberts et al, 2010; Shargorodsky et al, 2010). The development of tinnitus is strongly correlated with acoustic trauma and noise-induced hearing loss, the absence of tinnitus after exposure to loud sounds—resilience to tinnitus—has been observed in a significant percentage of the population both in humans and in animal models (Yankaskas, 2012; Zeng et al, 2012; Li et al, 2013). When bilateral DCN lesion occurred prior to noise exposure, it prevented the induction of tinnitus (Brozoski et al, 2012). These results suggest that DCN is not essential for the maintenance of tinnitus, it is indispensable for the induction of tinnitus
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